Cancers of the gastrointestinal tract comprise more than 10% of all cancers diagnosed in the U.S. (www.cancer.org). Disease incidence and phenotype are influenced by genetics and the environment. Although the number of people having colonoscopy screenings is increasing, the incidence of colorectal cancer has not decreased. Cancers of the small intestine total less than 5% of colorectal cancers, but the five year survival rate is very low. The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in Familial Adenomatous Polyposis (FAP), a dominant inherited disorder that predisposes individuals to developing colorectal cancer (Groden et al. 1991). Having FAP is also a risk factor for small intestinal cancer, as tumors tend to form at or near the duodenum in FAP patients. Mouse models of small intestine and colorectal cancers are invaluable for understanding the process of tumorigenesis and discovering mechanisms that interfere with progression to malignancy. The ApcMin/+ mouse contains a point mutation in the Apc gene that results in a truncated protein (Moser et al. 1990;Su et al. 1992). Genetic background has a significant role in determining the phenotypes of ApcMin/+ mice (reviewed in Siracusa et al. 2004) and complex trait analyses have identified several Modifier of Min (Mom) loci that alter intestinal tumor phenotypes (reviewed in Kwong and Dove 2008). This exploratory R21 is focused on using the ApcMin/+ mouse model to identify genes that influence tumor progression. The idea for this study arose when we had an exciting finding, namely that hybrid progeny from an intercross between inbred strains had a long lifespan and were highly resistant to tumor progression, even though they carried the ApcMin mutation. The few tumors that develop in these exceptional mice remain almost exclusively low grade adenomas and do not progress to more advanced stages. This model challenges the existing paradigm that tumor progression is a function of age. We, therefore, have a unique model system that mimics human disease in several ways: 1) the genome of these hybrid mice is heterozygous at virtually every locus (as is the case in humans), 2) the lifespan of these mice is comparable to humans 50 years of age and beyond (a risk factor for intestinal cancers), and 3) tumors develop without losing the entire chromosome carrying the Apc+ allele (a mechanism similar to human tumors). The factor responsible for resistance to progression appears limited to a single chromosome;our research is designed to define this modifier gene and pathways that protect against tumor progression. Translation of this work to human cancers could ultimately lead to better prevention and treatment options for intestinal cancers. PUBLIC HEALTH RELEVANCE: Many steps and changes along the way are responsible for turning a benign tumor growth into a life-threatening cancer. This research is designed to uncover genes that function during the intermediate steps of this process. The goal is to identify genes that can prevent the progression of tumors into cancers in the small intestine and colon. With this knowledge, we can move towards developing novel preventive and therapeutic options for patients.